There are several procedures for the production of the anthelmintic tetramisole reported in the literature (Raemaekers et al., J. Med. Chem. 9, 545 (1966), Bakelien et al., Aust. J. Chem. 21 1557 (1968), T. R. Roy U.S. Pat. No. 3,855,234, M. E. McMenin, U.S. Pat. No. 3,845,070). These procedures yield tetramisole, a racemic compound, which is then resolved to give its physiologically active levorotatory enantiomer levamisole. None of these procedures is adaptable to a direct synthesis of levamisole without resolution.
A method for making tetramisole from 1-(2-hydroxyethyl)-4-phenyl-4-imidazolin-2-thione and thionyl chloride is disclosed in U.S. Pat. No. 3,726,894. This compound is made by the hydroboration reaction on 1-vinyl-4-phenyl-4-imidazolin-2-thione, which is obtained as a by-product in the racemization of physiologically inactive d-tetramisole to the physiologically active dl-compound, tetramisole.
The literature reports two methods for the synthesis of levamisole without its resolution (Raeymaekers et al., Tetrahedron Letters, 1467 (1967) and P. R. Dick, French Pat. No. 2224-472).
The stereoselective synthesis of levamisole by the Raeymaekers method involves the condensation of optically active .alpha.-phenylethylenediamine with carbon disulfide, followed by the reaction of the resulting 4-phenyl-imidazolidine-2-thione with ethylene bromide. The synthesis requires optically active .alpha.-phenylethylenediamine, which has to be prepared by resolution. Thus resolution is not avoided, only placed back in the reaction sequence. The ring closure with ethylene bromide on the intermediate described would also produce some "isolevamisole" (2,3,4,5-tetrahydro-5-phenylimidazo(2,1-b)thiazole) which would have to be separated. No mention of this separation has been made in the above publication.
The second stereospecific synthesis of levamisole is disclosed in the above-mentioned French Patent. This involves the reaction of 2-substituted thiazolidines with optically active 2-phenylaziridine and subsequent ring closure. This synthesis also requires the preparation of the optically active intermediate 2-phenyl aziridine through a resolution procedure, and the condensation will also produce some undesired "isolevamisole", which must be separated. Additionally, the possible carcinogenicity of the 2-phenylaziridine (low molecular weight aziridines have proven carcinogenic) makes the process hazardous to run and requires extraordinary care to assure absence of the intermediate in the final product.
The instant invention overcomes all these drawbacks in that it is regioselective (no isolevamisole can be formed); all the steps occur in good yields; it involves for the first time in levamisole synthesis a catalytic reduction step, amenable to introducing chirality using catalytic amounts of a chiral reagent. The synthesis is even expected to be more economical than the current routes for tetramisole; and it is applicable to the synthesis of other analogs.